Regular Low-Dose Oral Metronidazole Is Associated With Fewer Vesicovaginal and Rectovaginal Fistulae in Recurrent Cervical Cancer: Results From a 10-Year Retrospective Cohort.

PURPOSE: Anaerobic necrosis in cervical cancer can lead to malodor, fistulae, and treatment abandonment. In this retrospective cohort study, we examined the association between maintenance metronidazole and the incidence of malignant fistulae in recurrent cervical cancer. METHODS: We screened all cervical cancer records registered between 2007 and 2016 in the local palliative care database at Christian Medical College, Vellore, India. There were 208 eligible patients with post-treatment residual/recurrent pelvic disease. Among them, 76 had received oral maintenance metronidazole 200 mg once per day for 2 to 86 weeks (interquartile range, 4-16 weeks). RESULTS: Seventy-two patients developed at least one fistula. Forty-nine had vesicovaginal fistulae, 10 had rectovaginal fistuale, and 13 developed both types of fistulae. Patients on maintenance metronidazole had fewer fistulae (22.4% v 41.7%; P = .005), a longer median fistula-free survival (42.9 months v 14.1 months; P < .001), and a postrecurrence survival of 11.5 months versus 8.7 months (P = .112). We performed Cox multivariable proportional hazards regression analysis on the data from the subset of 146 patients observed until death. Bladder/rectal infiltration had a higher risk of fistula (HR, 5.24; P = .011), whereas distant metastases (HR, 2.46; P = .012) and Eastern Cooperative Oncology Group performance status greater than 1 (HR, 1.64; P = .008) were associated with a higher risk of death. Maintenance metronidazole was associated with a lower risk of fistula (hazard ratio [HR], 0.33; 95% CI, 0.16 to 0.67; P = .002) and a lower risk of death (HR, 0.56; 95% CI, 0.39 to 0.81; P = .002). CONCLUSION: Our data indicate that there is a significant inverse association between oral maintenance metronidazole and malignant fistulae in locally recurrent cervical cancer. The impact of this simple intervention on pelvic symptoms, fistulae, and survival should be evaluated in prospective studies.

Stable gastric pentadecapeptide BPC 157 heals rectovaginal fistula in rats.

AIM: Rectovaginal fistula is a devastating condition providing more than 99% of patients for surgical treatment. We hypothesized that rectovaginal fistula may be healed by therapy with stable gastric pentadecapeptide BPC 157, in consistence with its initial clinical application and effect on external fistulas. MAIN METHODS: BPC 157 (10µg/kg or 10ng/kg) was given perorally, in drinking water (0.16µg/ml or 0.16ng/ml, 12ml/rat/day) till sacrifice, or alternatively, intraperitoneally, first application at 30min after surgery, last at 24h before sacrifice. Controls simultaneously received an equivolume of saline (5.0ml/kg ip) or water only (12ml/rat/day). The assessment (i.e., rectal and vaginal defect, fistula leakage, defecation through the fistula, adhesions and intestinal obstruction as healing processes) was at day 1, 3, 5, 7, 10, 14 and 21. KEY FINDINGS: Regularly, rectovaginal fistulas exhibited poor healing, with both of the defects persisting, continuous fistula leakage, defecation through the fistula, advanced adhesion formation and intestinal obstruction. By contrast, BPC 157 given perorally or intraperitoneally, in µg- and ng-regimens rapidly improved the whole presentation, with both rectal and vaginal defects simultaneously ameliorated and eventually healed. The maximal instilled volume was continuously raised till the values of healthy rats were achieved, there were no signs of defecation through the fistula. A counteraction of advanced adhesion formation and intestinal obstruction was achieved. Microscopic improvement was along with macroscopic findings. SIGNIFICANCE: BPC 157 effects appear to be suited to induce a full healing of rectovaginal fistulas in rats.

Nonsurgical management of a rectovaginal fistula caused by a Gellhorn pessary.

BACKGROUND: Pessaries are generally thought to be a safe, well-tolerated treatment for pelvic organ prolapse. CASE: An 85-year-old woman had a Gellhorn pessary placed for pelvic organ prolapse. Although she was seen regularly for care, the pessary had not been removed for several years. She presented stating that she felt the pessary had shifted. On examination, the patient's pessary stem had eroded through the vagina into the rectum. The pessary was removed and the patient was treated with vaginal estradiol cream. One month later the fistula tract had resolved and the patient continued to desire a pessary to manage her pelvic organ prolapse. CONCLUSION: Pessaries require care and maintenance. Patients' desires for conservative management should be coupled with education and routine follow-up.

Effectiveness and safety of local adalimumab injection in patients with fistulizing perianal Crohn's disease: a pilot study.

BACKGROUND: Various blockers of tumor necrosis factor-α are available for treatment of Crohn's disease. Randomized controlled trials have demonstrated the effects of systemic therapy with adalimumab, a fully humanized monoclonal antibody against tumor necrosis factor-α. OBJECTIVE: The aim of this study was to investigate the effectiveness and safety of local injection of adalimumab along the fistula in the treatment of perianal Crohn's disease. DESIGN AND SETTING: This was a prospective, uncontrolled, open-label observational study performed at a university tertiary care center. PATIENTS: A total of 12 outpatients (9 women, 3 men) treated for fistulizing perianal Crohn's disease between 2009 and 2010 were enrolled. The mean age was 43.5 (range, 27-59) years. The fistula was classified as anovaginal in 3 patients, transsphincteric in 7 patients (low in 2, high in 5), and complex (multiple tracts) in 2 patients. Pikarsky's Perianal Crohn's Disease Activity Index was used to evaluate severity of the perianal disease. INTERVENTION: Adalimumab was injected locally along the fistula tract and around the internal orifice every 2 weeks. MAIN OUTCOME MEASURES: The primary end point of the study was the proportion of patients in whom complete or improved healing of fistulas was observed at follow-up, with improvement based on the number of daily changes of sanitary pads. RESULTS: The median number of injections per patient was 7 (range, 4-16). The mean length of follow-up was 17.5 (range, 5-30) months; 75% of patients (9 of 12) reached complete cessation of fistula drainage, and 3 patients (25%), all with transsphincteric fistula, showed improvement. Comparison of overall follow-up scores on the Perianal Crohn's Disease Activity Index with baseline showed significant improvement (p = 0.002). No adverse side effects were noted. LIMITATIONS: The study was limited by its small sample size and by the absence of a control group. CONCLUSIONS: This pilot study suggests that a high local concentration of adalimumab favors prompt and definitive healing of the fistulous tract in patients with perianal Crohn's disease. Future randomized trials with well-defined selection criteria are needed to determine the relative risks and benefits of available anti-TNF-α blockers (chimeric vs fully humanized) and the optimal mode of administration (systemic use vs local injection) in the treatment of fistulizing perianal Crohn's disease.

Results of combined medical and surgical treatment of recto-vaginal fistula in Crohn's disease.

AIM: Surgical repair of recto-vaginal fistula (RVF) in Crohn's disease (CD) has been associated with high rates of failure. The aim of this study was to compare the outcome in patients with CD who underwent RVF surgery with or without infliximab infusion. METHOD: A retrospective review was carried out of 51 consecutive patients with CD treated for a symptomatic RVF between March 1998 and December 2004. RESULTS: Fifty-one patients (mean age 39 years) underwent 65 procedures, including seton drainage (n = 35), advancement flap (n = 8), fibrin glue injection (n = 8), transperineal repair (n = 6), collagen plug placement (n = 4) and bulbocavernosus flap (n = 4). All patients were on medical treatment at the time of surgery and 26 patients had received preoperative infliximab treatment (minimum of three infusions, 5 mg/kg). Ten patients underwent preoperative diversion. At a mean follow up of 38.6 months, 27 fistulas (53%) had healed and 24 (47%) had recurred. Fistula healing occurred in 60% of patients treated with preoperative diversion, whereas 51% of nondiverted repairs were successful. Neither active proctitis nor infliximab therapy significantly affected fistula healing. Fourteen (27%) patients eventually required proctectomy. CONCLUSION: RVF in CD is difficult to treat. Failure rates are significant despite repeated surgical interventions and concomitant medical treatment.

Rapid recovery of a rectovaginal fistula with infliximab in a patient with Crohn's disease.

We present the case of a female patient diagnosed with colonic Crohn's disease, having a clinical evolution with many recurrences and in whom conventional therapy had failed. The patient was admitted in our department 4 years after the onset of the disease, with an altered general state, diarrhea, malnutrition, fever and fecaloid vaginal discharge. Investigations classified the patient in a severe activity flare of Crohn's disease (CDAI 329), complicated with a rectovaginal fistula. Infliximab therapy was initiated. The evolution was rapidly favorable and the fistula closed after 4 weeks of therapy.

Outcome of surgery for rectovaginal fistula due to Crohn's disease.

BACKGROUND: This study examined the outcome of surgery for symptomatic Crohn's rectovaginal fistula (RVF) and assessed the effect of therapy with antibody against tumour necrosis factor (TNF) on healing. METHODS: Fifty-six patients with Crohn's disease underwent surgery for a RVF between January 1993 and December 2006. Outcome analysis was performed in February 2008 in relation to the surgical procedures used and the effect of anti-TNF treatment. RESULTS: Four patients with a healed fistula still had a stoma at final follow-up for other reasons and were excluded from the analysis. Fistula closure was achieved in 81 per cent of the remaining 52 patients. Primary and secondary surgical success rates were 56 and 57 per cent respectively. The primary healing rate was similar in patients who received anti-TNF treatment before the first operation (12 of 18 patients) and those who did not (19 of 34). In univariable analysis, duration of Crohn's disease (P = 0.037) and previous extended colonic resection (P < 0.001) were significantly related to failure of primary surgery, but only the latter remained significant in multivariable analysis (P < 0.001). Late recurrence developed in four patients. CONCLUSION: Fistula closure was achieved in most patients, but more than one operation was often required.

Complicated granulomatous colitis in a patient with Hermansky-Pudlak syndrome, successfully treated with infliximab.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder which is characterised by the triad of oculocutaneous albinism, platelet dysfunction and accumulation of ceroidlike pigment in tissues. Complications of the syndrome, such as fatal pulmonary fibrosis, renal failure and cardiomyopathy have been described. Granulomatous colitis has been documented in several families with the HPS. The bowel disease of the HPS is a unique type of inflammatory bowel disease with clinical features suggestive of idiopathic ulcerative colitis (UC) and pathologic features suggestive of Crohn's disease. We report a patient with HPS which was complicated by granulomatous colitis with perineal and rectovaginal fistulas refractory to antibiotics and azathioprine but dramatically responded to repeated infusions of infliximab.

Hepatocellular carcinoma occurring in a patient with Crohn's disease treated with both azathioprine and infliximab.

Hepatocellular carcinoma is known to be associated with underlying liver diseases, such as cirrhosis, hemochromatosis, and chronic viral hepatitis. All reported cases of hepatocellular carcinoma in association with Crohn's disease involve patients treated previously with azathioprine or both azathioprine and steroids. However, hepatocellular carcinoma associated with the use of azathioprine and infliximab has not been reported. In this report, we describe an unusual case of hepatocellular carcinoma and focal hepatic glycogenosis (FHG) occurring in a non-cirrhotic Crohn's disease patient who has been treated with both azathioprine and infliximab.

Perianal Crohn disease.

Crohn disease is a chronic inflammatory disease characterized by sharply demarcated segments of gastrointestinal involvement from mouth to anus. Its perineal manifestations are among the most devastating and mutilating complications. They occur at any time and may precede the intestinal manifestations. Their most common presentations are perineal ulceration, fistula, and abscess. Proliferative and polypoid morphology of the cutaneous lesions mimicking warts and condyloma are rarely described. We report a 25-year-old woman with a 4-month history of confluent plaques of the perineal region with vegetant surfaces, suspected to be genital warts. The lesions progressed to fistulas, inducing deep ulcerations surrounded by pseudocondylomatous tumors. About 2 months prior to presentation she began to suffer from gastrointestinal symptoms and noted weight loss. Physical examination, endoscopic examination, and pathological interpretation led to the diagnosis of Crohn disease with perineal involvement being the initial presenting sign. Significant improvement was induced with prednisone (45 mg daily) and azathioprine. Our observation is notable for the pseudocondylomatous appearance and the dramatic response to medical treatment despite severe involvement.

Infliximab therapy in 30 patients with refractory pediatric crohn disease with and without fistulas in The Netherlands.

OBJECTIVE: The purpose of this study was to describe the clinical experience with the anti-tumor necrosis factor chimeric monoclonal antibody, infliximab, in pediatric patients with Crohn disease in The Netherlands. DESIGN: Descriptive. METHODS: Clinical response and adverse effects of infliximab were recorded for pediatric patients with Crohn disease treated from October 1992 to January 2003. RESULTS: Thirty patients (aged 7-18 years) with refractory Crohn disease (with or without severe fistulas) were treated with infliximab. Patients were treated with up to 30 infusions. Mean follow-up was 25.3 months. A total of 212 infusions were administered. Thirteen patients had refractory Crohn disease without fistulas. Six patients showed good long-term response to infliximab treatment (defined as clinical index < or =10 points). Sixteen patients had refractory Crohn disease with draining fistulas. Nine showed good long-term response (closure or nonproductiveness of fistulas). One patient with metastatic Crohn disease in the skin had a good long-term response. Six patients developed an allergic reaction during infusion. In one patient, the allergic reaction occurred after an infliximab-free interval of 9 years. One patient died of sepsis. CONCLUSIONS: Infliximab was an effective therapy in 53% of patients with refractory pediatric Crohn disease, with or without fistulas. Approximately half of the patients become unresponsive to infliximab therapy. Randomized controlled studies are mandatory to assess long-term efficacy and safety to define the optimal therapeutic strategy of infliximab therapy in children with Crohn disease.

Perianal fistulae following infliximab treatment: clinical and endosonographic outcome.

BACKGROUND: Management of perianal and rectovaginal fistulae complicating Crohn's disease (CD) is unsatisfactory. Infliximab is effective in the treatment of fistulating CD. However, reopening of fistulae is frequent, suggesting the persistence of deep fistula tracts despite superficial healing. In this study, the clinical and endosonographic behavior of perianal fistulae were evaluated following infliximab infusions, as well as the role of anal endosonography (AE) in predicting their outcome. METHODS: Thirty CD patients presenting with perianal and/or rectovaginal fistulae received an infusion of infliximab at a dose of 5 mg/kg at weeks 0 (entry into the study), 2, and 6. Laboratory and clinical assessments were repeated at same intervals and at week 10. AE was performed at entry and at week 10. Thereafter, the perianal region was re-examined every 6 months, and patients were investigated regarding draining of the fistula in the previous months. RESULTS: Fifteen patients (53.6%) showed closure of the fistulae at week 10, but only 5 patients had the fistula tracts disappeared at AE. Clinical and AE closure of rectovaginal fistulae was less prevalent than that of perianal fistulae [14.3% versus 63.6% at week 6 (p = 0.035); 28.6% versus 59.1% at week 10 (p = 0.21); 14.3% versus 22.7% at AE (p = 1.00)]. The behavior of fistulae was not affected by their number and AE classification, presence of rectal disease, or setons. Twenty patients with perianal fistulae were followed for a median of 15.5 months. Patients with closed perianal fistulae at week 10 and disappearance of fistulae tract at AE showed a lower relapse rate than those with endosonographic persistence of fistula tract. CONCLUSIONS: Infliximab can heal perianal and rectovaginal fistulae in approximately 60% and 30% of patients, respectively. Despite closure, most fistula tracts are still detectable at AE. Persistence of the internal tract is a condition at higher risk of fistula recurrence.

Clinical and radiological responses after infliximab treatment for perianal fistulizing Crohn's disease.

OBJECTIVES: Infliximab is an effective therapy for fistulizing Crohn's disease of the perineum. We sought to determine whether the clinical improvement after infliximab is associated with radiological closure of fistula tracts. METHODS: Clinical responses and radiological imaging studies by transperineal ultrasound were evaluated in 35 patients with Crohn's disease perianal fistulas after treatment with infliximab 5 mg/kg up to 48 wk. Paired comparison of baseline and follow-up imaging studies at 8 wk and at 56 wk or discontinuation were assessed by an imaging score of perianal fistula severity, based on the Parks criteria. Complete clinical fistula closure and radiological healing were primary outcome measures. RESULTS: At 8 wk, after two infusions of infliximab at 0 and 2 wk, clinical fistula closure occurred in 49% of patients. The radiological score at 8 wk was higher for patients with clinical fistula closure than for patients with no clinical improvement (p= 0.023) and two patients showed complete radiological healing. At 56 wk, clinical fistula closure occurred in 46% patients. Clinical fistula scores correlated with radiological scores (R2= 0.52; p < 0.001) but were not associated with fistula complexity, number of fistulas, or number of collections at baseline imaging. The proportion of patients with marked radiological improvement increased from 14% at 8 wk to 43% at 56 wks (p= 0.015) and complete radiological healing occurred in 4 (11%) patients. CONCLUSIONS: For perianal fistulizing Crohn's disease, repeat dose infliximab improves clinical and radiological outcomes, although complete radiological healing occurs in a minority of patients.